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1.  Methylglyoxal as a new biomarker in patients with septic shock: an observational clinical study 
Critical Care  2014;18(6):683.
The role of reactive carbonyl species, such as methylglyoxal (MG), has been overlooked within the context of the sepsis syndrome. The aims of this study were to assess the impact of MG formation in different inflammatory settings and to evaluate its use for early diagnosis as well as prognosis of the sepsis syndrome.
In total, 120 patients in three groups were enrolled in this observational clinical pilot study. The three groups included patients with septic shock (n = 60), postoperative controls (n = 30), and healthy volunteers (n = 30). Plasma samples from patients with septic shock were collected at sepsis onset and after 24 hours and 4, 7, 14, and 28 days. Plasma samples from postoperative controls were collected prior to surgery, immediately following the end of the surgical procedure as well as 24 hours later and from healthy volunteers once. Plasma levels of MG were determined by high-performance liquid chromatography. Additionally, plasma levels of procalcitonin, C-reactive protein, soluble CD14 subtype, and interleukin-6 were determined.
Patients with septic shock showed significantly higher plasma levels of MG at all measured times, compared with postoperative controls. MG was found to identify patients with septic shock more effectively—area under the curve (AUC): 0.993—than procalcitonin (AUC: 0.844), C-reactive protein (AUC: 0.791), soluble CD14 subtype (AUC: 0.832), and interleukin-6 (AUC: 0.898) as assessed by receiver operating characteristic (ROC) analysis. Moreover, plasma levels of MG in non-survivors were significantly higher than in survivors (sepsis onset: *P = 0.018 for 90-day survival; **P = 0.008 for 28-day survival). Plasma levels of MG proved to be an early predictor for survival in patients with septic shock (sepsis onset: ROC-AUC 0.710 for 28-day survival; ROC-AUC 0.686 for 90-day survival).
MG was identified as a marker for monitoring the onset, development, and remission of sepsis and was found to be more useful than routine diagnostic markers. Further studies are required to determine the extent of MG modification in sepsis and whether targeting this pathway could be therapeutically beneficial to the patient.
Trial registration
German Clinical Trials Register DRKS00000505. Registered 8 November 2010.
Electronic supplementary material
The online version of this article (doi:10.1186/s13054-014-0683-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4301657  PMID: 25498125
2.  Long-term (20- to 25-year) Results of an Uncemented Tapered Titanium Femoral Component and Factors Affecting Survivorship 
Uncemented femoral components in primary total hip arthroplasty (THA) are commonly used today, but few studies have evaluated their survival into the third decade.
We evaluated (1) survivorship using femoral revision for any reason as the end point; (2) survivorship using femoral revision for aseptic loosening as the end point; and (3) patient-related and surgical risk factors for aseptic stem loosening at a minimum 20-year followup with an uncemented tapered titanium stem.
We reviewed the clinical and radiographic results of 354 THAs in 326 patients performed between January 1985 and December 1989 using an uncemented grit-blasted, tapered titanium femoral stem. Mean age at surgery was 57 years (range, 13–81 years). Kaplan-Meier survivorship analysis was used to estimate long-term survival. Minimum followup evaluation was 20 years (mean, 22 years; range, 20–25 years); at that time, 120 patients (127 hips) had died, and four patients (five hips) were lost to followup. Multivariate survival analysis using a Cox regression model was performed.
Survivorship at 22 years with revision of the femoral component for any reason as the end point was 86% (95% confidence interval [CI], 81%–90%). Survivorship for femoral revision for aseptic loosening as the end point was 93% at 22 years (95% CI, 90%–96%). Undersized stems (canal fill index ≤ 80%) and stems in hips with cup revision were at higher risk for aseptic loosening (hazard ratio, 4.2 and 4.3, respectively). There was a high rate of acetabular revision in this series (38%), mostly related to smooth-threaded, cementless sockets.
Uncemented femoral fixation was reliable into the third decade. Age, male sex, and diagnosis were not associated with a higher risk of aseptic loosening.
Level of Evidence
Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC3773148  PMID: 23670671
3.  Sleep-disordered breathing is a risk factor for delirium after cardiac surgery: a prospective cohort study 
Critical Care  2014;18(5):477.
Delirium is a frequent complication after cardiac surgery. Although various risk factors for postoperative delirium have been identified, the relationship between nocturnal breathing disorders and delirium has not yet been elucidated. This study evaluated the relationship between sleep-disordered breathing (SDB) and postoperative delirium in cardiac surgery patients without a previous diagnosis of obstructive sleep apnea.
In this prospective cohort study, 92 patients undergoing elective cardiac surgery with extracorporeal circulation were evaluated for both SDB and postoperative delirium. Polygraphic recordings were used to calculate the apnea-hypopnea index (AHI; mean number of apneas and hypopneas per hour recorded) of all patients preoperatively. Delirium was assessed during the first four postoperative days using the Confusion Assessment Method. Clinical differences between individuals with and without postoperative delirium were determined with univariate analysis. The relationship between postoperative delirium and those covariates that were associated with delirium in univariate analysis was determined by a multivariate logistic regression model.
The median overall preoperative AHI was 18.3 (interquartile range, 8.7 to 32.8). Delirium was diagnosed in 44 patients. The median AHI differed significantly between patients with and without postoperative delirium (28 versus 13; P = 0.001). A preoperative AHI of 19 or higher was associated with an almost sixfold increased risk of postoperative delirium (odds ratio, 6.4; 95% confidence interval, 2.6 to 15.4; P <0.001). Multivariate logistic regression analysis showed that preoperative AHI, age, smoking, and blood transfusion were independently associated with postoperative delirium.
Preoperative SDB (for example, undiagnosed obstructive sleep apnea) were strongly associated with postoperative delirium, and may be a risk factor for postoperative delirium.
Electronic supplementary material
The online version of this article (doi:10.1186/s13054-014-0477-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4175616  PMID: 25189637
4.  Spinal bone metastases in gynecologic malignancies: a retrospective analysis of stability, prognostic factors and survival 
The aim of this retrospective study was to evaluate the stability of spinal metastases in gynecologic cancer patients (pts) on the basis of a validated scoring system after radiotherapy (RT), to define prognostic factors for stability and to calculate survival.
Fourty-four women with gynecologic malignancies and spinal bone metastases were treated at our department between January 2000 and January 2012. Out of those 34 were assessed regarding stability using the Taneichi score before, 3 and 6 months after RT. Additionally prognostic factors for stability, overall survival, and bone survival (time between first day of RT of bone metastases and death from any cause) were calculated.
Before RT 47% of pts were unstable and 6 months after RT 85% of pts were stable. Karnofsky performance status (KPS) >70% (p = 0.037) and no chemotherapy (ChT) (p = 0.046) prior to RT were significantly predictive for response. 5-year overall survival was 69% and 1-year bone survival was 73%.
RT is capable of improving stability of osteolytic spinal metastases from gynecologic cancer by facilitating re-ossification in survivors. KPS may be a predictor for response. Pts who received ChT prior to RT may require additional bone supportive treatment to overcome bone remodeling imbalance. Survival in women with bone metastases from gynecologic cancer remains poor.
PMCID: PMC4163163  PMID: 25182126
Bone metastases; Spine; Gynecologic malignancies; Stability; Radiotherapy
5.  10-year results of the uncemented Allofit press-fit cup in young patients 
Acta Orthopaedica  2014;85(4):368-374.
Background and purpose
Uncemented acetabular components in primary total hip arthroplasty (THA) are commonly used today, but few studies have evaluated their survival into the second decade in young and active patients. We report on a minimum 10-year follow-up of an uncemented press-fit acetabular component that is still in clinical use.
We examined the clinical and radiographic results of our first 121 consecutive cementless THAs using a cementless, grit-blasted, non-porous, titanium alloy press-fit cup (Allofit; Zimmer Inc., Warsaw, IN) without additional screw fixation in 116 patients. Mean age at surgery was 51 (21–60) years. Mean time of follow-up evaluation was 11 (10–12) years.
At final follow-up, 8 patients had died (8 hips), and 1 patient (1 hip) was lost to follow-up. 3 hips in 3 patients had undergone acetabular revision, 2 for deep infection and 1 for aseptic acetabular loosening. There were no impending revisions at the most recent follow-up. We did not detect periacetabular osteolysis or loosening on plain radiographs in those hips that were evaluated radiographically (n = 90; 83% of the hips available at a minimum of 10 years). Kaplan-Meier survival analysis using revision of the acetabular component for any reason (including isolated inlay revisions) as endpoint estimated the 11-year survival rate at 98% (95% CI: 92–99).
Uncemented acetabular fixation using the Allofit press-fit cup without additional screws was excellent into early in the second decade in this young and active patient cohort. The rate of complications related to the liner and to osteolysis was low.
PMCID: PMC4105767  PMID: 24875058
6.  Quality of life and fatigue of patients with spinal bone metastases under combined treatment with resistance training and radiation therapy- a randomized pilot trial 
The aim of this trial was to compare the effects of resistance training versus passive physical therapy on quality of life (QoL), fatigue, and emotional distress outcomes during radiation therapy in patients with spinal bone metastases under radiotherapy (RT).
In this randomized trial, 60 patients were treated from September 2011 until March 2013 into one of the two groups: isometric resistance training or physical therapy with thirty patients in each group during RT. EORTC QLQ-BM22, EORTC QLQ-FA13, and FBK-R10 were assessed at baseline, three months, and six months after RT.
Psychosocial aspects in resistance training group (Arm A) were significantly improved after three (p = 0.001) and six months (p = 0.010). Other rated items of the QLQ-BM22 painful site, and pain characteristics were without significant differences. Functional interference showed a positive trend after six months (p = 0.081). After six months, physical fatigue (p = 0.013), and interference with daily life (p = 0.006) according to the QLQ-FA13 assessment improved in Arm A significantly. Emotional distress was in Arm A lower after six months (p = 0.016). The Cohen’s effect size confirmed the clinically significant improvement of these findings.
In this group of patients we were able to show that guided isometric resistance training of the paravertebral muscles can improve functional capacity, reduce fatigue and thereby enhance QoL over a 6-months period in patients with stable spinal metastases. The results offer a rationale for future large controlled investigations to confirm these findings.
Trial registration
Clinical trial identifier NCT01409720
PMCID: PMC4105868  PMID: 24998293
7.  Pain response of resistance training of the paravertebral musculature under radiotherapy in patients with spinal bone metastases – a randomized trial 
BMC Cancer  2014;14:485.
To compare pain response outcomes for patients with spinal bone metastases treated with resistance training of the spinal musculature versus passive physical therapy during radiotherapy (RT).
In this randomized trial, 60 consecutive patients were treated from September 2011 until March 2013 within one of the two groups: resistance training (Arm A) or passive physical therapy (Arm B) with thirty patients in each group during RT. The course of pain according to visual analog scale (VAS), concurrent medication, and oral morphine equivalent dose (OMED) were assessed at baseline, three months, and six months after RT. Pain response was determined using International Bone Consensus response definitions.
The course of VAS in the intervention group (Arm A) was significantly lower both during and after RT (AUC, p < .001). The use of analgetic medication showed the same result, with significantly fewer analgetics being necessary both during and after RT in arm A (p < .001). In the course of time, the OMED decreased in arm A, but increased in arm B. After 6 month, 72.2% of patients in arm A, and 22.2% in arm B were responders (p = .014).
Our trial demonstrated that guided isometric resistance training of the paravertebral muscles can improve pain relief over a 6-months period in patients with stable spinal metastases. Importantly, the intervention was able to reduce OMED as well as concomitant pain medication. The trial is registered in Clinical trial identifier NCT 01409720 ( since 2nd of August 2011.
PMCID: PMC4094419  PMID: 24996223
Bone metastases; Spine; Physical exercise; Pain response; Isometric muscle training; Palliative radiotherapy
8.  Quality of life, fatigue and local response of patients with unstable spinal bone metastases under radiation therapy - a prospective trial 
To evaluate the local response according to stability after radiotherapy (RT) with a special focus on quality-of-life (QoL), fatigue, pain and emotional distress in patients with unstable spinal bone metastases.
In this prospective trial, 30 patients were treated from September 2011 until March 2013. The stability of osteolytic metastases in the thoracic and lumbar spine was evaluated on the basis of the Taneichi-score after three and six months. EORTC QLQ-BM22, EORTC QLQ-FA13, and QSC-R10 were assessed at baseline, and three months after RT.
After 3 months, 25% (n = 6) and after 6 months 33.3% (n = 8) were classified as stable. QoL, fatigue, and emotional distress showed no difference over the course. The pain response 3 months after RT showed a significant difference (p < 0.001). Pathological fractures occurred in 8.3% of the patients (n = 2) within six months following RT.
Our trial demonstrated that RT can improve stability in one third of patients over a 6-months period with unstable spinal metastases. Importantly, for these patients pain relief was detected but RT had no impact on QoL, fatigue, and emotional distress.
Trial registration
Clinical trial identifier NCT01409720.
PMCID: PMC4060071  PMID: 24917420
Bone metastases; Spine; Stability; Unstable metastases; Palliative radiotherapy
9.  Randomized controlled trial to evaluate the effects of ethyl-2-cyanoacrylate on pain intensity and quality of life in head and neck cancer patients suffering from cetuximab-induced rhagades during radioimmunotherapy: the support trial 
BMC Cancer  2014;14:270.
Cetuximab is a chimeric monoclonal antibody against the epidermal growth factor receptor (EGFR). Skin reactions are the most common side effects of cetuximab. Rhagades of the tips of the fingers and toes, the heels and especially the interphalangeal joints are one of the most frightening and painful dermatological side effects that may develop from EGFR-inhibitor therapy. Rhagades are characterized by pain, severe tenderness and poor healing response. They are challenging to treat. Thus, rhagades often poses the most significant threat to the quality of life (QoL) for these patients. Ethyl-2-cyanoacrylate (ECA), an ethyl ester of the 2-cyano-2-propenoic acid, is often used as adhesive in a variety of different work settings in industry, i.e. as a component in nail-care products such as nail glue. In addition, ECA is used for various medical indications, such as for liquid bandages and for suture-less surgery. Wound healing can be accelerated with ECA. The purpose of the SUPPORT trial is to investigate the efficacy of ECA for the treatment of cetuximab-induced rhagades and to assess the clinical usefulness of the SUPO score, a new classification system for rhagades induced by EGFR-inhibitor therapy.
The SUPPORT trial is an open-label, prospective, randomized, national multicenter intervention study to evaluate the effectiveness of ECA versus the standard treatment of each institution on the pain intensity and QoL in patients with locally advanced head and neck cancer suffering from painful cetuximab-induced rhagades during radioimmunotherapy. Primary endpoint is the assessment of the pain intensity 24 hours after application of ECA or the standard treatment quantified by the visual analogue scale (VAS). Secondary endpoints are the evaluation of QoL assessed by the EORTC-QoL-C30 questionnaire and the Dermatological Life Quality Index (DLQI).
During treatment with EGFR inhibitors it is necessary to recognize and manage side effects promptly to assure better patient QoL. The SUPPORT trial is the first randomized clinical trial evaluating a new treatment option for painful cetuximab-induced rhagades. Furthermore, the new SUPO score will be prospectively assessed in terms of clinical usefulness for classification of EGFR inhibitor-induced rhagades.
Trial registration
Current Controlled Trials NCT01693159.
PMCID: PMC4051406  PMID: 24742019
10.  Prevalence and determinants of osteoporosis in patients with type 1 and type 2 diabetes mellitus 
Increased risk of osteoporosis and its clinical significance in patients with diabetes is controversial. We analyze osteoporosis prevalence and determinants of bone mineral density (BMD) in patients with type 1 and 2 diabetes.
Three hundred and ninety-eight consecutive diabetic patients from a single outpatient clinic received a standardized questionnaire on osteoporosis risk factors, and were evaluated for diabetes-related complications, HbA1c levels, and lumbar spine (LS) and femoral neck (FN) BMD. Of these, 139 (71 men, 68 women) type 1 and 243 (115 men, 128 women) type 2 diabetes patients were included in the study. BMD (T-scores and values adjusted for age, BMI and duration of disease) was compared between patient groups and between patients with type 2 diabetes and population-based controls (255 men, 249 women).
For both genders, adjusted BMD was not different between the type 1 and type 2 diabetes groups but was higher in the type 2 group compared with controls (p < 0.0001). Osteoporosis prevalence (BMD T-score < −2.5 SD) at FN and LS was equivalent in the type 1 and type 2 diabetes groups, but lower in type 2 patients compared with controls (FN: 13.0% vs 21.2%, LS: 6.1% vs 14.9% men; FN: 21.9% vs 32.1%, LS: 9.4% vs 26.9% women). Osteoporosis prevalence was higher at FN-BMD than at LS-BMD. BMD was positively correlated with BMI and negatively correlated with age, but not correlated with diabetes-specific parameters (therapy, HbBA1c, micro- and macrovascular complications) in all subgroups. Fragility fracture prevalence was low (5.2%) and not different between diabetes groups. Fracture patients had lower BMDs compared with those without fractures; however, BMD T-score was above −2.5 SD in most patients.
Diabetes-specific parameters did not predict BMD. Fracture occurrence was similar in both diabetes groups and related to lower BMD, but seems unrelated to the threshold T-score, <−2.5 SD. These results suggest that osteoporosis, and related fractures, is a clinically significant and commonly underestimated problem in diabetes patients.
PMCID: PMC4021186  PMID: 24721668
Bone mineral density; Diabetes mellitus; Fractures; Osteoporosis; Vascular complications
11.  Stability of spinal bone metastases in breast cancer after radiotherapy 
Strahlentherapie Und Onkologie  2014;190(9):792-797.
This retrospective analysis was performed to evaluate osteolytic bone lesions of breast cancer in the thoracic and lumbar spine after radiotherapy (RT) in terms of stability using a validated scoring system.
The stability of 157 osteolytic metastases, treated from January 2000 to January 2012, in 115 patients with breast cancer was evaluated retrospectively using the Taneichi score. Predictive factors for stability were analyzed and survival rates were calculated.
Eighty-five (54 %) lesions were classified as unstable prior to RT. After 3 and 6 months, 109 (70 %) and 124 (79 %) lesions, respectively, were classified as stable. Thirty fractures were detected prior to RT, and after RT seven cases (4.5 %) with pathologic fractures were found within 6 months. None of the examined predictive factors showed significant correlation with stability 6 months after RT. After a median follow-up of 16.7 months, Kaplan–Meier estimates revealed an overall survival of 83 % after 5 years.
The majority of patients showed an improved or unchanged stability of the involved vertebral bodies after 6 months. The patients showed only minor cancer-related morbidity during follow-up and reached comparably high survival rates.
PMCID: PMC4141967  PMID: 24687563
Bone metastases; Spine; Breast cancer; Stability; Fracture; Knochenmetastasen; Wirbelsäule; Brustkrebs; Stabilität; Fraktur
12.  Incidence of perioperative sleep-disordered breathing in patients undergoing major surgery: a prospective cohort study 
Major surgery might have a modulating effect on nocturnal breathing patterns. The incidence and course of perioperative sleep-disordered breathing in individuals without a previous diagnosis of obstructive sleep apnea has not been investigated sufficiently so far.
In this study, polygraphic recordings have been obtained from 37 inpatients without a diagnosis of obstructive sleep apnea syndrome during the preoperative night before and six nights following major surgical procedures.
Eligible patients consenting to participate in this study underwent polygraphic recordings including four items (O2-saturation, pulse, nasal air flow and snoring) during the study period. Polygraphic data obtained from the postoperative recordings were compared to preoperative recordings.
Median (IQR [range]) apnea-hypopnea-index (AHI) for the whole group was 6,0 (2,5 - 14,7 [0–32,6]) in the preoperative night and increased in the following six nights post surgery: second night: 5,6 (2,6-15,0 [1,1 - 59,3]); third night: 16,9 (5,6 - 38,8 [2,9 - 64,3]); fourth night: 11,6 (5,9 - 17,3 [0,4 - 39,3]); fifth night: 15,2 (5,7 - 22,2 [0,2 - 55,5]); sixth night: 22,5 (5,2 - 35,4 [0,2 - 67,7]). AHI-scores of the third to sixth night post surgery differed significantly from data observed in the preoperative night.
A significant increase in the AHI occurred frequently after major surgical procedures in the late postoperative period. Sleep-disordered breathings in the late postoperative period deserve attention, as they potentially increase the risk of postoperative complications.
PMCID: PMC3995597  PMID: 24624978
Obstructive sleep apnea; Major surgery; Sleep-disordered breathing; Postoperative hypoxemia
13.  Feasibility of isometric spinal muscle training in patients with bone metastases under radiation therapy - first results of a randomized pilot trial 
BMC Cancer  2014;14:67.
Spinal bone metastases are commonly diagnosed in cancer patients. The consequences are pain both at rest and under exercise, impairment of activities of daily life (ADL), reduced clinical performance, the risk of pathological fractures, and neurological deficits. The aim of this randomized, controlled pilot trial was to investigate the feasibility of muscle-training exercises in patients with spinal bone metastases under radiotherapy. Secondary endpoints were local control, pain response and survival.
This study was a prospective, randomized, monocentre, controlled explorative intervention trial to determine the multidimensional effects of exercises for strengthening the paravertebral muscles. On the days of radiation treatment, patients in the control group were physically treated in form of respiratory therapy. Sixty patients were randomized between September 2011 and March 2013 into one of the two groups: differentiated resistance training or physical measure with thirty patients in each group.
The resistance training of the paravertebral muscles was feasible in 83.3% of patients (n = 25). Five patients died during the first three months. The exercise group experienced no measurable side effects. “Chair stand test” in the intervention group was significant enhanced with additionally improved analgesic efficiency. Patients in intervention group improved in pain score (VAS, 0–10) over the course (p < .001), and was significant better between groups (p = .003) after 3 months. The overall pain response showed no significant difference between groups (p = .158) There was no significant difference in overall and bone survival (survival from first diagnosed bone metastases to death).
Our trial demonstrated safety and feasibility of an isometric resistance training in patients with spinal bone metastases. The results offer a rationale for future large controlled investigations to confirm these findings.
Trial registration
Clinical trial identifier NCT01409720.
PMCID: PMC3923729  PMID: 24499460
Bone metastases; Spine; Physical exercise; Stability; Isometric training
14.  A retrospective comparative exploratory study on two Methylentetrahydrofolate Reductase (MTHFR) polymorphisms in esophagogastric cancer: the A1298C MTHFR polymorphism is an independent prognostic factor only in neoadjuvantly treated gastric cancer patients 
BMC Cancer  2014;14:58.
Methylentetrahydrofolate reductase (MTHFR) plays a major role in folate metabolism and consequently could be an important factor for the efficacy of a treatment with 5-fluorouracil. Our aim was to evaluate the prognostic and predictive value of two well characterized constitutional MTHFR gene polymorphisms for primarily resected and neoadjuvantly treated esophagogastric adenocarcinomas.
569 patients from two centers were analyzed (gastric cancer: 218, carcinoma of the esophagogastric junction (AEG II, III): 208 and esophagus (AEG I): 143). 369 patients received neoadjuvant chemotherapy followed by surgery, 200 patients were resected without preoperative treatment. The MTHFR C677T and A1298C polymorphisms were determined in DNA from peripheral blood lymphozytes. Associations with prognosis, response and clinicopathological factors were analyzed retrospectively within a prospective database (chi-square, log-rank, cox regression).
Only the MTHFR A1298C polymorphisms had prognostic relevance in neoadjuvantly treated patients but it was not a predictor for response to neoadjuvant chemotherapy. The AC genotype of the MTHFR A1298C polymorphisms was significantly associated with worse outcome (p = 0.02, HR 1.47 (1.06-2.04). If neoadjuvantly treated patients were analyzed based on their tumor localization, the AC genotype of the MTHFR A1298C polymorphisms was a significant negative prognostic factor in patients with gastric cancer according to UICC 6th edition (gastric cancer including AEG type II, III: HR 2.0, 95% CI 1.3-2.0, p = 0.001) and 7th edition (gastric cancer without AEG II, III: HR 2.8, 95% CI 1.5-5.7, p = 0.003), not for AEG I. For both definitions of gastric cancer the AC genotype was confirmed as an independent negative prognostic factor in cox regression analysis. In primarily resected patients neither the MTHFR A1298C nor the MTHFR C677T polymorphisms had prognostic impact.
The MTHFR A1298C polymorphisms was an independent prognostic factor in patients with neoadjuvantly treated gastric adenocarcinomas (according to both UICC 6th or 7th definitions for gastric cancer) but not in AEG I nor in primarily resected patients, which confirms the impact of this enzyme on chemotherapy associated outcome.
PMCID: PMC3922603  PMID: 24490800
Esophagogastric adenocarcinoma; Prognostic factors; Folate metabolism; Methylentetrahydrofolate reductase; Genetic polymorphisms; C677T; A1298C
15.  Neurological outcome after emergency radiotherapy in MSCC of patients with non-small cell lung cancer - a prospective trial 
The aim of this trial was to investigate neurological outcome after emergency RT in MSCC of NSCLC patients with acute neurological deficit.
This pilot trial was prospective, non-randomized, and monocentre, ten patients were treated from July 2012 until June 2013. After onset of neurological symptoms RT was started within 12 hours. The neurological outcome was assessed at baseline, and six weeks after RT using the ASIA Impairment Scale (AIS).
The results showed an improved neurological outcome in one patient (10%), one patient (10%) had a decreased, and five patients (50%) a constant outcome after six weeks. Three patients (30%) died within the first six weeks following RT, additional 4 patients (40%) died within 4 month due to tumor progression.
In this group of NSCLC patients we were able to show that emergency RT in MSCC with acute neurological deficit had no considerable benefit in neurological outcome. Therefore, short-course regime or best supportive care due to poor survival should be considered for these patients with additional distant metastases. Patients with favorable prognosis may be candidates for long-course RT.
Trial Registration
Clinical trial identifier NCT 02000518.
PMCID: PMC3904469  PMID: 24373638
Emergency radiotherapy; MSCC; Spine; Neurological outcome
16.  DISCOVER trial– Distal resection of the pancreas with or without coverage of the pancreatic remnant: study protocol of a randomised controlled trial 
Trials  2013;14:430.
Distal pancreatectomy for benign and malignant tumours is the second most common surgical procedure on the pancreas. Postoperative pancreatic fistulas (POPF) represent the most significant clinical complication, causing prolongation of hospital stay and the need for additional diagnostic and therapeutic procedures. Although various techniques for preventing POPF have been evaluated, to date, there is no available technique that ensures closure of the pancreatic remnant.
DISCOVER will aim to investigate differences in the postoperative course after a distal pancreatectomy comparing the standard surgical technique with an alternative technique that provides additional coverage of the pancreatic remnant by the falciform ligament. The primary endpoint of this trial will be the rate of POPF. As secondary endpoints, incidence of postoperative morbidity and mortality, length of hospital stay, and quality of life will be assessed.
DISCOVER is a single-centre, randomised, controlled surgical trial. For statistical analysis, a binary logistic regression model will be used. With a level of significance of 5% and a power of 80%, a sample size of 75 patients per group has been identified as necessary.
The findings of this trial will help to evaluate the usefulness of the coverage procedure at reducing the rate of POPF. The results could influence the standard procedure for remnant closure after distal pancreatectomy.
Clinical trials register (DRKS-ID: DRKS00000546)
PMCID: PMC3867413  PMID: 24330450
Coverage procedure; Distal pancreatectomy; Falciform ligament; Pancreatic fistula
17.  Regular three-dimensional presentations improve in the identification of surgical liver anatomy – a randomized study 
BMC Medical Education  2013;13:131.
Three-dimensional (3D) presentations enhance the understanding of complex anatomical structures. However, it has been shown that two dimensional (2D) “key views” of anatomical structures may suffice in order to improve spatial understanding. The impact of real 3D images (3Dr) visible only with 3D glasses has not been examined yet. Contrary to 3Dr, regular 3D images apply techniques such as shadows and different grades of transparency to create the impression of 3D.
This randomized study aimed to define the impact of both the addition of key views to CT images (2D+) and the use of 3Dr on the identification of liver anatomy in comparison with regular 3D presentations (3D).
A computer-based teaching module (TM) was used. Medical students were randomized to three groups (2D+ or 3Dr or 3D) and asked to answer 11 anatomical questions and 4 evaluative questions. Both 3D groups had animated models of the human liver available to them which could be moved in all directions.
156 medical students (57.7% female) participated in this randomized trial. Students exposed to 3Dr and 3D performed significantly better than those exposed to 2D+ (p < 0.01, ANOVA). There were no significant differences between 3D and 3Dr and no significant gender differences (p > 0.1, t-test). Students randomized to 3D and 3Dr not only had significantly better results, but they also were significantly faster in answering the 11 anatomical questions when compared to students randomized to 2D+ (p < 0.03, ANOVA). Whether or not “key views” were used had no significant impact on the number of correct answers (p > 0.3, t-test).
This randomized trial confirms that regular 3D visualization improve the identification of liver anatomy.
PMCID: PMC3848999  PMID: 24066729
18.  Impact of preoperative patient education on prevention of postoperative complications after major visceral surgery: study protocol for a randomized controlled trial (PEDUCAT trial) 
Trials  2013;14:271.
In line with the growing number of surgical procedures being performed worldwide, postoperative complications are also increasing proportionately. Prevention of these postoperative complications is a high medical priority. Preoperative education of patients, including provision of preparatory information about the correct behavior after surgery, could improve the postoperative outcome, but the evidence for this is inconclusive. The aim of the PEDUCAT trial is to evaluate the feasibility and the impact of preoperative patient education on postoperative morbidity, mortality and quality of life in patients scheduled for elective major visceral surgery.
PEDUCAT is designed as a cluster-randomized controlled pilot study. The experimental group will visit a standardized preoperative seminar to learn how best to behave after surgery in addition to being given a standard information brochure, whereas the control group will only receive the information brochure. Outcome measures such as postoperative morbidity, postoperative pain, postoperative anxiety and depression, patient satisfaction, quality of life, length of hospital stay and postoperative mortality will be evaluated. Statistical analysis will be based on the intention-to-treat population. Analysis of covariance will be applied for the intervention group comparison, adjusting for age, center and quality of life before surgery. This is a pilot study to show the feasibility of the concept. Nevertheless, the planned sample size of n = 204 is large enough to show an effect with power of 90% and a significance level of 5%.
Trial registration
German Clinical Trial Register number: DRKS00004226.
PMCID: PMC3765330  PMID: 23978275
Patient education; Preoperative education; Postoperative complication; Prevention; Visceral surgery; Cluster randomization
19.  The stability of osseous metastases of the spine in lung cancer – a retrospective analysis of 338 cases 
The objective of this retrospective analysis is to systematically assess osseous lesions on the basis of a validated scoring system in terms of stability and fractures prior to and following radiotherapy in 338 lung cancer patients with bone metastases in the vertebral column.
The stability of 338 patients with 981 osteolytic metastases in the thoracic and lumbar spine was evaluated retrospectively on the basis of the Taneichi-Score between January 2000 and January 2012.
64% (215 patients) were classified stable prior to radiotherapy. Of the stable osseous metastases, none were rated unstable in the further course (p < 0.001, McNemar test). Of the 123 patients in whom the metastases were classified unstable prior to radiotherapy, 21 patients (17%) were classified stable after three months, and 30 patients (24%) stable after six months. A pathological fracture was diagnosed in 62 patients (18%) prior to radiotherapy. Regarding cases of osteolytic metastases of the vertebral bodies in which no fractures could be detected prior to the start of therapy, fractures occurred in 2% of all patients (n = 7) within six months following radiotherapy.
Our analysis demonstrated that pathological fractures following radiotherapy occur in the very minority of vertebral lesions for patients with a favorable outcome. The use of a systematic radiological scoring system to classify osteolytic metastases of the vertebral column has shown to be feasible in daily routine. Prospective clinical trials are warranted in order to analyse, to what extent patients with osseous metastases can be mobilized by physiotherapy for strengthening the paravertebral muscles before radiotherapy effects can be measured by means of radiological recalcification.
PMCID: PMC3751223  PMID: 23937907
Bone metastases; Spine; Lung cancer; Stability; Fracture
20.  Reactive Metabolites and AGE-RAGE-Mediated Inflammation in Patients following Liver Transplantation 
Mediators of Inflammation  2013;2013:501430.
Recent investigations have indicated that reactive metabolites and AGE-RAGE-mediated inflammation might play an important role in the pathogenesis of ischemia-reperfusion injury in liver transplantation. In this observational clinical study, 150 patients were enrolled following liver transplantation from deceased donors. The occurrence of short-term complications within 10 days of transplantation was documented. Blood samples were collected prior to transplantation, immediately after transplantation, and at consecutive time points, for a total of seven days after transplantation. Plasma levels of methylglyoxal were determined using HPLC, whereas plasma levels of L-arginine, asymmetric dimethylarginine, advanced glycation endproducts-carboxylmethyllysine, soluble receptor for advanced glycation endproducts, and total antioxidant capacity were measured by ELISA. Patients following liver transplantation were shown to suffer from increased RAGE-associated inflammation with an AGE load mainly dependent upon reactive carbonyl species-derived AGEs. In contrast, carboxylmethyllysine-derived AGEs were of a minor importance. As assessed by the ratio of L-arginine/asymmetric dimethylarginine, the bioavailability of nitric oxide was shown to be reduced in hepatic IRI, especially in those patients suffering from perfusion disorders following liver transplantation. For the early identification of patients at high risk of perfusion disorders, the implementation of asymmetric dimethylarginine measurements in routine diagnostics following liver transplantation from deceased donors should be taken into consideration.
PMCID: PMC3677670  PMID: 23766560
21.  Pylorus resection or pylorus preservation in partial pancreatico-duodenectomy (PROPP study): study protocol for a randomized controlled trial 
Trials  2013;14:44.
Partial pancreatico-duodenectomy (PD) is the standard treatment for tumors of the pancreatic head. Today, preservation of the pylorus has been widely accepted as the surgical standard in this procedure. A common postoperative complication is the occurrence of delayed gastric emptying (DGE), which causes impairment of oral intake andpatients’ quality of life, prolongation of hospital stay and delay of further treatment (for example adjuvant chemotherapy). In a small number of two retrospective and one randomized studies, a modification by resection of the pylorus with preservation of the stomach has shown to reduce DGE incidence. The aim of the present study is to investigate the effect of pylorus resection on postoperative DGE in PD.
Patients undergoing elective PD for any indication equal or older than 18 years and who have given informed consent will be included. Patients will be randomized to either PD with pylorus preservation or PD with pylorus resection and complete stomach preservation. Sample size (n = 89 patients per group) is calculated on an assumed difference in DGE incidence of 20%. Primary study endpoint is DGE within 30 days; secondary endpoints are operation time, blood loss, morbidity, mortality, hospital stay and quality of life (QoL).
DGE is a relevant clinical problem following PD with a great impact on patients’ recovery, length of hospital stay, QoL and consecutive adjuvant therapies. As there is no causal therapy, prevention of DGE is essential to improve outcome. The technical modification of pylorus resection may offer a simple and effective method for this purpose. The present study is designed to increase the existing body of evidence and potentially change the future standard surgical procedure of PD.
Trial registration
German Clinical Trials Register DRKS00004191.
PMCID: PMC3599830  PMID: 23410208
Partial pancreatico-duodenectomy; Pylorus preservation; Pylorus resection; Randomized trial
22.  Design and current status of CONTINT: continuous versus interrupted abdominal wall closure after emergency midline laparotomy - a randomized controlled multicenter trial [NCT00544583] 
Trials  2012;13:72.
The optimal strategy for abdominal wall closure has been an issue of ongoing debate. Available studies do not specifically enroll patients who undergo emergency laparotomy and thus do not consider the distinct biological characteristics of these patients. The present randomized controlled trial evaluates the efficacy and safety of two commonly applied abdominal wall closure strategies in patients undergoing primary emergency midline laparotomy.
The CONTINT trial is a multicenter, open label, randomized controlled trial with a two-group parallel design. Patients undergoing a primary emergency midline laparotomy are enrolled in the trial. The two most commonly applied strategies of abdominal wall closure after midline laparotomy are compared: the continuous, all-layer suture technique using slowly absorbable monofilament material (two Monoplus® loops) and the interrupted suture technique using rapidly absorbable braided material (Vicryl® sutures). The primary endpoint within the CONTINT trial is an incisional hernia within 12 months or a burst abdomen within 30 days after surgery. As reliable data on this primary endpoint is not available for patients undergoing emergency surgery, an adaptive interim analysis will be conducted after the inclusion of 80 patients, allowing early termination of the trial if necessary or modification of design characteristics such as recalculation of sample size.
This is a randomized controlled multicenter trial with a two-group parallel design to assess the efficacy and safety of two commonly applied abdominal wall closure strategies in patients undergoing primary emergency midline laparotomy.
Trial registration
PMCID: PMC3536720  PMID: 22647387
23.  L-Arginine and Asymmetric Dimethylarginine Are Early Predictors for Survival in Septic Patients with Acute Liver Failure 
Mediators of Inflammation  2012;2012:210454.
Dysfunctions of the L-arginine (L-arg)/nitric-oxide (NO) pathway are suspected to be important for the pathogenesis of multiple organ dysfunction syndrome (MODS) in septic shock. Therefore plasma concentrations of L-arg and asymmetric dimethylarginine (ADMA) were measured in 60 patients with septic shock, 30 surgical patients and 30 healthy volunteers using enzyme linked immunosorbent assay (ELISA) kits. Plasma samples from patients with septic shock were collected at sepsis onset, and 24 h, 4 d, 7 d, 14 d and 28 d later. Samples from surgical patients were collected prior to surgery, immediately after the end of the surgical procedure as well as 24 h later and from healthy volunteers once. In comparison to healthy volunteers and surgical patients, individuals with septic shock showed significantly increased levels of ADMA, as well as a decrease in the ratio of L-arg and ADMA at all timepoints. In septic patients with an acute liver failure (ALF), plasma levels of ADMA and L-arg were significantly increased in comparison to septic patients with an intact hepatic function. In summary it can be stated, that bioavailability of NO is reduced in septic shock. Moreover, measurements of ADMA and L-arg appear to be early predictors for survival in patients with sepsis-associated ALF.
PMCID: PMC3352626  PMID: 22619480
24.  Pancreatogastrostomy versus pancreatojejunostomy for RECOnstruction after partial PANCreatoduodenectomy (RECOPANC): study protocol of a randomized controlled trial UTN U1111-1117-9588 
Trials  2012;13:45.
Pancreatoduodenectomy is one of the most complex abdominal operations, usually performed for tumors of the periampullary region and chronic pancreatitis. Leakage of pancreatic juice from the pancreatoenteric anastomosis, called postoperative pancreatic fistula, is the most prominent postoperative complication. Retrospective studies show a significant reduction of fistula rates with pancreatogastrostomy as compared to pancreatojejunostomy, the most frequently employed method of pancreatoenterostomy. Most single-center prospective trials, however, have not validated this finding. A large multicenter trial is needed for clarification.
RECOPANC is a prospective, randomized, controlled multicenter trial with two treatment arms, pancreatogastrostomy versus pancreatojejunostomy. The trial hypothesis is that postoperative pancreatic fistula rate is lower after pancreatogastrostomy when compared to pancreatojejunostomy. Fourteen academic centers for pancreatic surgery will participate to allocate 360 patients to the trial. The duration of the entire trial is four years including prearrangement and analyses.
Postoperative pancreatic fistula is the main reason for clinically important postoperative morbidity after pancreatoduodenectomy. The primary goal of the chosen reconstruction technique for pancreatoenteric anastomosis is to minimize postoperative fistula rate. A randomized trial performed at multiple high-volume centers for pancreatic surgery is the best opportunity to investigate one of the most crucial issues in pancreatic surgery.
Trial registration
German Clinical Trials Register DRKS00000767 (2011/03/23), FSI 2011/05/31. Universal Trial Number U1111-1117-9588.
PMCID: PMC3478188  PMID: 22540372
Pancreatic fistula; Pancreatoduodenectomy; Pancreatogastrostomy
25.  To whom do the results of the multicenter, randomized, controlled INSECT trial (ISRCTN 24023541) apply? - assessment of external validity 
BMC Surgery  2012;12:2.
A response to Seiler et al: Interrupted or continuous slowly absorbable sutures for closure of primary elective midline abdominal incisions: a multicenter randomized trial (INSECT: ISRCTN24023541). Ann Surg 2009, 249(4):576-582.
Existing evidence suggests that the transfer of results of randomized controlled trials into clinical practice may be limited. Potential reasons can be attributed to aspects of external validity. The aim of this study is to investigate issues related to the external validity of the INSECT trial.
All participating surgical departments were categorized and the clinical and baseline characteristics of randomized patients were evaluated. In addition, demographic and clinical data of all screened and randomized patients at the Departments of Surgery in Heidelberg and Erlangen were analyzed.
Twenty-five centers enrolled a total of 625 patients. These centers included eight primary, 11 secondary, and six tertiary care centers. The tertiary care centers enrolled the most patients (n = 237, 38%) followed by the primary care centers (n = 199, 32%) and the secondary care centers (n = 189 patients; 30%). The mean number and baseline data of randomized patients did not differ between the three types of care centers (p = 0.09). Overall, the treatment according to protocol was at least 92%. At the Department of Surgery, University of Heidelberg, 307 patients were screened and 60 out of 130 eligible patients were randomized. There were no differences in demographic and clinical baseline data between included and non-included patients. In Erlangen, 351 patients were screened and 57 out of 106 eligible patients randomized.
Results of the INSECT trial are applicable to a broad spectrum of patients treated at different hospital levels.
PMCID: PMC3328288  PMID: 22316122

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